PulmCrit- Can we fix a broken circadian clock with melatonin?

Normal Physiology: Circadian rhythm

Circadian rhythm refers to synchronization of the body's physiology with external day-night cycles. It’s an evolutionarily ancient adaptive mechanism seen in species ranging from plants to fruit flies to humans.

The circadian rhythm is generated by the hypothalamus and pineal gland. Light is the primary input to this system, entraining the circadian rhythm. The output from this system is melatonin secreted by the pineal gland. Melatonin levels peak at night, signaling the presence of night to organs throughout the body.

Circadian rhythms and melatonin are best known for their relationship to sleep. However, they have a much broader range of functions. Circadian rhythms cause many organs to enter a resting state at night (e.g. heart rate decreases, cortisol levels increase).

Pathophysiology: Circadian derangement & delirium in the ICU

ICU patients are often exposed to light, noise, and pain at night. It comes as no surprise that patients frequently have circadian rhythm derangement (e.g. insomnia, daytime somnolence).1 Physiologically, this is reflected in loss of a normal pattern of melatonin secretion, especially loss of nocturnal peaks.2345 Melatonin depletion may be particularly associated with mechanical ventilation and sepsis.678

Circadian rhythm disruption may be dangerous. In the absence of circadian rhythms, some patients may remain stuck in a physiologically aroused state. This may cause deprivation of sleep, excessive inflammation, and persistent cardiovascular stress. Other patients may develop an inverted circadian rhythm with daytime somnolence, preventing them from obtaining high-quality sleep or participating in physical therapy.

The most obvious complication of circadian derangement is delirium. The brain requires restorative, high-quality sleep to function. Sleep deprivation and fragmentation will inevitably lead to delirium, even in otherwise healthy people. Many physicians trained before the era of work-hour restrictions have experienced this personally (including yours truly).9

Several studies have correlated the development of delirium with loss of cyclical melatonin secretion.10 For example, a prospective observational study among hospitalized patients showed that loss of melatonin secretion precedes the development of delirium by three days – suggesting a potential causative role.11

Evidence regarding melatonin agonists to prevent delirium

RCTs evaluating delirium prevention12

Melatonin agonists might restore normal circadian rhythmicity. This makes them attractive targets for the prevention and treatment of delirium. Four placebo-controlled RCTs shown below evaluated the ability of melatonin agonists to prevent delirium among mixed patient cohorts.13141516 Studies solely involving post-operative delirium aren’t included here, because the physiology of post-operative delirium may be unique.1718 Furthermore, studies on surgical populations may suffer from problems sorting out true delirium versus normal emergence from anesthesia.

A rudimentary Forrest plot above shows results from these studies along with the combined data (which simply reflects pooling together all of the patients).19 Most studies found benefit from melatonin agonists. Jaiswal was discordant with the other studies, possibly for the following reasons:16

Patients in Jaiswal et al were healthier, with a lower rate of delirium overall. The reduced incidence of delirium in this study decreased its power (note that power depends on both the sample size and the frequency of events).

The median length of stay was only three days, which is shorter than the other studies. This may be too soon to see the effects of circadian derangement or benefit from melatonin agonists.

This was a double-blind RCT involving 82 patients who had been intubated for >48 hours in a medical-surgical ICU.20 Patients were randomized to receive placebo versus 6 mg of melatonin nightly (3 mg at 8 PM plus 3 mg at midnight).

The primary endpoint was the amount of hydroxyzine administered (hydroxyzine is an antihistamine they used insomnia). Melatonin did indeed cause a significant reduction in hydroxyzine administration (p<0.01), as well as propofol administration. In parallel with weaning off sedatives, melatonin also hastened weaning from mechanical ventilation:

This data can be interpreted in various different ways. Perhaps melatonin directly reduced delirium, and thereby hastened recovery. Alternatively, melatonin may have merely reduced the use of deleriogenic medications (e.g. hydroxyzine). Regardless, melatonin improved clinical outcomes.

Evidence summary

Five RCTs evaluated the ability of melatonin agonists to prevent delirium or optimize sleep. Four detected benefit, whereas one was neutral. None of the studies detected significant harm. These trials are small, with larger RCTs underway. However, they strongly suggest that the benefits of treatment outweigh risks.

Melatonin may be preferable to ramelteon

Melatonin and ramelteon are very similar agents. There is no clear data on which drug is superior. Currently, melatonin may be preferable for the following reasons:

(1) Impressive track record for safety

Melatonin is available over-the-counter in the United States, being used by about 3.5 million Americans.23 Despite broad exposure of the populace, severe side-effects don’t seem to be an issue. Allergy to melatonin cannot exist. The only well-documented side effect is drowsiness (which might be beneficial among patients on mechanical ventilation who require sedation).20 Clinical trials using huge doses of melatonin (e.g. 1,000 mg/day) haven’t detected additional side-effects. Although some articles list minor side-effects from melatonin (e.g. headache), placebo-controlled trials don’t find a difference in side effects when rigorously comparing melatonin versus placebo.24

(2) Cost & availability

Melatonin is widely available. It’s extremely cheap, with a dose costing well under a dollar. In contrast, the cost of an episode of delirium in the ICU can easily exceed thousands of dollars (e.g. by delaying extubation and prolonging ICU length of stay). Thus, even if melatonin is only marginally effective in reducing delirium, it will be cost-effective.

Ideal melatonin dose?

The ideal melatonin dose in the ICU is unknown. To make matters more confusing, the ideal therapeutic strategy is unclear. One could imagine various strategies:

Physiologic replacement: Some patients simply lose melatonin production in the ICU. For these patients, it could make sense to give a low dose of melatonin which would generate physiogically normal levels.

Overdrive suppression: Some patients will develop a phase-shifted circadian rhythm in the ICU (e.g. sundowning). In such patients, it could make sense to give a supraphysiologic dose of melatonin at night, to overpower the deranged endogenous circadian rhythm.

The dose of melatonin studied in clinical trials varies between 0.5 to 6 mg. Among critically ill patients, a 10 mg dose results in supra-physiologic morning levels.25 A systematic review focusing on elderly outpatients suggested an optimal dose of 0.3-2 mg.26 Until further research is available, roughly 1-3 mg QHS may be reasonable.

ICU patients commonly suffer from disruption of circadian rhythms, with loss of nocturnal melatonin peaks. This correlates with delirium and poor clinical outcomes.

Exogenous melatonin supplementation is cheap and safe (it’s available over-the-counter).

Several small RCTs of melatonin agonists have been performed. Four of five studies detected benefit, with the fifth study being relatively underpowered. The most strongly supported benefit is delirium prevention.

The use of melatonin in the ICU remains under investigation, with further RCTs pending. At this point in time, available evidence suggests that the benefits of melatonin outweigh potential harms (which seem to be minimal).

Related

Nishikimi 2018 RCT (The Bottom Line) – I would have written more about this study but The Bottom Line already covered it nicely, so please see their site for further discussion.

Once during my training, I was awake for 50 hours consecutively (weekend call). At the end of that period I could function but lost the ability to maintain attention. When writing a patient note I would start a sentence, fall asleep for a second, wake up, and there would be a string of random words on the page. Despite numerous attempts I was unable to write coherently. .

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Comment Here

my problem with melatonin (for my personal use and by extension for the ICU) is the lack of standardization/proof of potency/safety of formulation secondary to the fact that it is a supplement rather than a medication. The only allure of ramelteon is that you are actually using what you think you are using. Does your pharmacy stock melatonin, if so how do they reconcile the above

My pharmacy stocks melatonin in 3 mg tabs from GenDose Pharmaceuticals, Cornelius NC. That seems like a fairly reputable source and I trust my pharmacists to do their homework with regards to suppliers. That said, ramelteon is a fine option if you don’t have melatonin on formulary (or if you want a higher level of standardization, proof of potency etc). Incidentally if the dose of melatonin is off slightly it won’t really matter, probably anywhere between 1mg-6mg of melatonin would be OK.

The Dietary Supplement Health and Education Act of 1994 (“DSHEA”), is a 1994 statute of United States Federal legislation which defines and regulates dietary supplements. Under the act, supplements are effectively regulated by the FDA for Good Manufacturing Practices. Under the act, supplement manufacturers do not need to receive FDA approval before marketing dietary supplements that were marketed in the United States before 1994. This means, except for new ingredients, they are presumed to be safe and they do not require FDA approval or review before they are marketed. The dietary supplement manufacturer (not the FDA) is responsible for making sure the supplements they sell are of high quality and safe to consume. Many supplement companies have excellent quality assurance, but some do not. In order to ensure the safety and quality of dietary supplements the USP program was created. The USP is a non-profit organization that tests and reports on the quality of supplements through its USP Dietary Supplement Verification Program. Although not part of government, USP standards are recognized in US Law and USP works closely with the U.S. Food and Drug Administration (FDA).. USP Verified means the supplement: 1. Contains the ingredients listed on the label, in… Read more »

What's Your Job?

Contemplater

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5 months ago

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Robert Chasse, MD

I have similar concerns regarding the variability in quality control in the supplement industry. For melatonin in particular see PMID: 27855744, PMID: 28095978. The limited data on melatonin in the ICU are tantalizing but fall short of convincing. It would seem that a multi-center trial would not be that hard but who would pony up the money? I cannot even get ramelteon added to my hospital formulary. Boarded in sleep as well as critical care

This study sampled random products off of grocery store shelves in Canada (some of which were mixed sleep-inducing concoctions with lots of bizarre ingredients). For the record I would *not* recommend this as a procurement strategy for melatonin. Gummy bears may taste good, but it turns out that they probably aren’t the best vehicle for melatonin. It’s unclear what (if anything) this says about the melatonin being sold at reputable pharmaceutical companies in the USA.

What's Your Job?

intensivist

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5 months ago

Guest

Robert Chasse, MD

same companies/types of companies are pushing their wares in this country. agree that we would not consider the “concoctions” for hospital use but supplement industry in this country is the wild wild west and the profit motive often trumps morality USP or not. On a positive note larger trials apparently are being done.. perhaps a real answer in the not too distant future.
Burry L, Scales D, Williamson D, et al Feasibility of melatonin for prevention of delirium in critically ill patients: A protocol for a multicentre, randomised, placebo-controlled study. BMJ Open 2017; 7:e015420